4O91

Crystal Structure of type II inhibitor NG25 bound to TAK1-TAB1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.39 Å
  • R-Value Free: 
    0.207 (Depositor), 0.210 (DCC) 
  • R-Value Work: 
    0.177 (Depositor), 0.180 (DCC) 
  • R-Value Observed: 
    0.179 (Depositor) 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted NG2Click on this verticalbar to view details

This is version 1.4 of the entry. See complete history


Literature

Discovery of Type II Inhibitors of TGF beta-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2).

Tan, L.Nomanbhoy, T.Gurbani, D.Patricelli, M.Hunter, J.Geng, J.Herhaus, L.Zhang, J.Pauls, E.Ham, Y.Choi, H.G.Xie, T.Deng, X.Buhrlage, S.J.Sim, T.Cohen, P.Sapkota, G.Westover, K.D.Gray, N.S.

(2015) J Med Chem 58: 183-196

  • DOI: https://doi.org/10.1021/jm500480k
  • Primary Citation of Related Structures:  
    4O91

  • PubMed Abstract: 

    We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure-activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16 and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. A 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors.


  • Organizational Affiliation

    Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 chimera314Homo sapiensMutation(s): 0 
Gene Names: MAP3K7MAP3K7 TAK1 TAB1 MAP3K7IP1TAK1
EC: 2.7.11.25
UniProt & NIH Common Fund Data Resources
Find proteins for Q15750 (Homo sapiens)
Explore Q15750 
Go to UniProtKB:  Q15750
PHAROS:  Q15750
GTEx:  ENSG00000100324 
Find proteins for O43318 (Homo sapiens)
Explore O43318 
Go to UniProtKB:  O43318
PHAROS:  O43318
GTEx:  ENSG00000135341 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsO43318Q15750
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NG2
Query on NG2

Download Ideal Coordinates CCD File 
B [auth A]N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzamide
C29 H30 F3 N5 O2
SMPGEBOIKULBCT-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.39 Å
  • R-Value Free:  0.207 (Depositor), 0.210 (DCC) 
  • R-Value Work:  0.177 (Depositor), 0.180 (DCC) 
  • R-Value Observed: 0.179 (Depositor) 
Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.214α = 90
b = 132.905β = 90
c = 145.498γ = 90
Software Package:
Software NamePurpose
HKL-3000data collection
PHASERphasing
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted NG2Click on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-30
    Type: Initial release
  • Version 1.1: 2014-10-08
    Changes: Database references
  • Version 1.2: 2015-01-28
    Changes: Database references
  • Version 1.3: 2017-08-02
    Changes: Refinement description, Source and taxonomy
  • Version 1.4: 2024-02-28
    Changes: Data collection, Database references, Derived calculations